Type I interferon target revealed
Posted: Fri Jun 06, 2008 3:20 pm
Nature Reviews Immunology 8, 402 (June 2008) | doi:10.1038/nri2339
Sarah Allan
AutoimmunityType I interferon target revealed
Treatment with interferon-beta (IFNbeta) reduces disease exacerbation in many patients with multiple sclerosis, but how this cytokine inhibits autoimmune inflammation in the central nervous system (CNS) is largely unknown. Now, Prinz, Kalinke and colleagues have revealed that the effect of type I IFNs on myeloid cells is crucial to the protective effect of this cytokine in the relevant animal model of experimental autoimmune encephalomyelitis (EAE).
Investigation of the expression of IFNbeta in mice with EAE revealed elevated levels of this cytokine in the CNS, but not the blood, of mice with active disease. Mice deficient in type I IFN receptor (IFNAR; Ifnar1- /- mice), developed more severe EAE, characterized by a greater degree of demyelination and increased lethality.
IFNAR is expressed by nearly all cell types and tissues, so it has been a challenge to evaluate the specific effects of type I IFNs in the context of EAE. As EAE is known to be a T-cell-mediated disease, the effect of type I IFNs on lymphocytes was investigated. Interestingly, the balance between T helper 1 (TH1)- and TH17-cell responses was unchanged in Ifnar1- /- mice with EAE, and specific ablation of Ifnar1 in either T cells or B cells had no effect on the course of the disease. Moreover, the lack of IFNAR expression by CNS tissue cells had no impact on EAE severity, indicating that the protective effects of type I IFNs in CNS inflammation are mediated by neither lymphocytes nor CNS-resident cells. However, specific ablation of Ifnar1 in myeloid cells resulted in significant aggravation of the effector phase of EAE, with elevation of pro-inflammatory mediators including tumour-necrosis factor and chemokines. Closer investigation revealed that exposure to IFNbeta reduced myelin uptake and impaired the upregulation of MHC class II molecules by macrophages, thereby inhibiting their activation state and antigen-presenting capacity.
So, this study has revealed a non-redundant role for myeloid cells in type I IFN-mediated protection of autoimmune inflammation in the CNS. This work provides clues as to how IFNbeta therapy might work in patients with multiple sclerosis and could help to develop more cell-specific therapies that reduce the side effects of the treatment.
Sarah Allan
AutoimmunityType I interferon target revealed
Treatment with interferon-beta (IFNbeta) reduces disease exacerbation in many patients with multiple sclerosis, but how this cytokine inhibits autoimmune inflammation in the central nervous system (CNS) is largely unknown. Now, Prinz, Kalinke and colleagues have revealed that the effect of type I IFNs on myeloid cells is crucial to the protective effect of this cytokine in the relevant animal model of experimental autoimmune encephalomyelitis (EAE).
Investigation of the expression of IFNbeta in mice with EAE revealed elevated levels of this cytokine in the CNS, but not the blood, of mice with active disease. Mice deficient in type I IFN receptor (IFNAR; Ifnar1- /- mice), developed more severe EAE, characterized by a greater degree of demyelination and increased lethality.
IFNAR is expressed by nearly all cell types and tissues, so it has been a challenge to evaluate the specific effects of type I IFNs in the context of EAE. As EAE is known to be a T-cell-mediated disease, the effect of type I IFNs on lymphocytes was investigated. Interestingly, the balance between T helper 1 (TH1)- and TH17-cell responses was unchanged in Ifnar1- /- mice with EAE, and specific ablation of Ifnar1 in either T cells or B cells had no effect on the course of the disease. Moreover, the lack of IFNAR expression by CNS tissue cells had no impact on EAE severity, indicating that the protective effects of type I IFNs in CNS inflammation are mediated by neither lymphocytes nor CNS-resident cells. However, specific ablation of Ifnar1 in myeloid cells resulted in significant aggravation of the effector phase of EAE, with elevation of pro-inflammatory mediators including tumour-necrosis factor and chemokines. Closer investigation revealed that exposure to IFNbeta reduced myelin uptake and impaired the upregulation of MHC class II molecules by macrophages, thereby inhibiting their activation state and antigen-presenting capacity.
So, this study has revealed a non-redundant role for myeloid cells in type I IFN-mediated protection of autoimmune inflammation in the CNS. This work provides clues as to how IFNbeta therapy might work in patients with multiple sclerosis and could help to develop more cell-specific therapies that reduce the side effects of the treatment.